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US4238423A - Process for preparing cyclo-1,3,2-oxazaphosphoryl derivatives - Google Patents

Process for preparing cyclo-1,3,2-oxazaphosphoryl derivatives Download PDF

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Publication number
US4238423A
US4238423A US06/091,786 US9178679A US4238423A US 4238423 A US4238423 A US 4238423A US 9178679 A US9178679 A US 9178679A US 4238423 A US4238423 A US 4238423A
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US
United States
Prior art keywords
acid
group
formula
sub
oxazaphosphoryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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US06/091,786
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English (en)
Inventor
Tadao Sato
Hiraki Ueda
Kazuyuki Nakagawa
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring

Definitions

  • the present invention relates to a novel process for preparing cyclo-1,3,2-oxazaphosphoryl derivatives. More particularly the present invention relates to a novel process for preparing cyclo-1,3,2-oxazophosphoryl derivatives represented by the formula (II), ##STR3## wherein R 2 and R 3 are respectively a lower alkyl group which may have halogen atom(s) or lower alkanesulfonyloxy group(s) as substituted group(s), and n stands for an integer of 2 to 6, by acid-cleaving the N--R 1 bond of 3-( ⁇ -arylalkyl)-cyclo-1,3,2-oxazaphosphoryl derivatives represented by the formula (I), ##STR4## wherein R 1 stands for an ⁇ -arylalkyl group, and R 2 , R 3 and n are the same as defined above.
  • the above mentioned known method has defects such that the method necessities an expensive catalyst for catalytic reduction, requires an extensive length of reaction time such as 10 hours or longer, and also requires a relatively high reaction temperature such as 50° C. or higher, which induces the decomposition of a relatively unstable cyclophosphamide once formed to result in a low yield of the desired compound.
  • the present inventors have made an extensive studies for finding a method for preparing the compound of the formula (II) which would be carried out easily and under more mild condition without incurring such defects of the prior arts.
  • the present inventors have now found out a novel method for preparing the compound of formula (II), the method being carried out by cleaving the N--R 1 bond of the compounds of the formula (I) in a relatively shorter reaction time and at a lower reaction temperature by using an acid. This leads to the accomplishment of the present invention on the basis of such the new knowledge of the cleavage method of N--R 1 bond.
  • the starting compound of the formula (I) is either a known compound or a compound readily prepared according to any known method.
  • a compound of the general formula (I) can easily be prepared through the following reaction scheme: ##STR6## wherein R 1 , R 2 and R 3 are the same as defined above, and X is a halogen atom.
  • a compound represented by the general formula (Ia) as prepared by the above process can easily be isolated into an optical isomer form of the general formula (Ib), if necessary.
  • the ⁇ -arylalkyl group as shown as R 1 herein is exemplified as ⁇ -arylalkyl group having a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as benzyl, ⁇ -phenylethyl, ⁇ -phenylpropyl, ⁇ -phenylbutyl, ⁇ -phenylhexyl, ⁇ -naphtylmethyl, ⁇ -naphthylmethyl, ⁇ -( ⁇ -naphthyl)ethyl, ⁇ -( ⁇ -naphthyl)-ethyl or the like.
  • An electron donative substituent may be replaced on the aryl ring of the ⁇ -arylalkyl group.
  • Said substituent may be, for example, a halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxy group.
  • said ⁇ -arylalkyl group having an asymmetric carbon atom may be of optical isomer or racemate.
  • the halogen atom may be fluorine, chlorine, bromine, or iodine atom.
  • an alkanesulfonyloxy group having a straight or branched alkyl group having 1 to 6 carbon atoms is exemplified, such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, isopropanesulfonyloxy, butanesulfonyloxy, tert-butanesulfonyloxy and hexanesulfonyloxy or the like.
  • a straight or branched alkyl group may be exemplified, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl group or the like.
  • the lower alkoxy group a straight or branched chain alkoxy group having 1 to 6 carbon atoms is exemplified, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, hexyloxy or the like.
  • R 2 or R 3 which may have a halogen atom or lower alkanesulfonyl group as a substituent
  • the followings are exemplified: for example, lower alkyl group as mentioned above, 2-chloroethyl, 3-chloropropyl, 4-chlorobutyl, 6-chlorohexyl, 2-bromoethyl, 2-fluoroethyl, 2-chloropropyl, 2,2-dimethyl-2-chloroethyl, 2-methanesulfonyloxyethyl, 3-methanesulfonyloxypropyl, 4-ethanesulfonyloxybutyl, 6-methanesulfonloxyhexyl, 4-butanesulfonyloxybutyl group or the like.
  • the process of the present invention can be carried out in the absence or presence of a solvent.
  • a solvent usable in the present invention
  • water a lower fatty acid such as formic acid, acetic acid, propionic acid or the like
  • an aromatic hydrocarbon such as benzene, toluene, xylene or the like
  • a saturated hydrocarbon such as n-hexane, cyclohexane, isooctane, or the like
  • an ether such as diethylether, 1,2-dimethoxyethane, anisole, or the like
  • a halogenated hydrocarbon such as methylene chloride, 1,2-dichloroethane or the like
  • sulfuric acid, fluorosulfuric acid, trifluoroacetic acid, perchloric acid, hydrogen bromide, methanesulfuric acid, trifluoromethanesulfonic acid or the like can be exemplified.
  • sulfuric acid, trifluoroacetic acid, hydrogen bromide trifluoromethanesulfonic acid and fluorosulfuric acid are preferred, and sulfuric acid having a concentration of 70% or higher is especially preferred.
  • Those acid can be used in an amount from catalytic amount to large excess amounts, and ordinarily equimolar amount to about 20 times of molar quantity of the compound of the general formula (I) are preferably used.
  • the reaction of the present invention is carried out at a temperature of -30° to 50° C., preferably at -15° C. to a room temperature and for 1 minute to 1 hour, ordinarily for 5 to 30 minutes.
  • the present invention is characterized in carrying out the reaction under such a moderate condition.
  • an inorganic acid salt such as ammonium sulfate or sodium sulfate may be added to the reaction system, and thereby the coloring of the reaction product can be avoided and improvement of yield can be attained.
  • the objective compound of the formula (I) can be easily purified after the reaction by using a conventional separation method, for example dilution with solvent, solvent extraction or recrystallization or the like.
  • the compound represented by the formula (II) obtained by the process of the present invention is a known compound and is useful as an anticancer agent.
  • ( ⁇ )-cyclophosphamide has been used as anticancer agent and S(-)-cyclophosphamide and R(+)-cyclophosphamide have been known to have anti-cancer activity [P. J. Cox, et al.: Biochemical Pharmacology, 25, 993-996 (1976), Pergamon Press, printed in Great Britain].
  • the existance of the substances A and B in the respective fractions were determined by thin layer chromatography, at which the chromatogram was developed by iodine vapor.
  • the trichloromethane layer was dried with anhydrous magnesium sulfate and the solvent was distilled off to obtain the crude crystals of S(-)-cyclophosphamide.
  • the crystals were recrystallized from either to obtain S(-)-cyclophosphamide in colorless prism-like crystals.
  • Example 1 such compounds of the general formula (II) as shown in Table were obtained.
  • the trichloromethane layer was dried with anhydrous magnesium sulfate and the solvent was removed by distillation to obtain crude crystals of S(-)-cyclophosphamide.
  • the crystals were recrystallized from ether to obtain S(-) -cyclophosphamide in colorless prism-like crystals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US06/091,786 1978-11-07 1979-11-06 Process for preparing cyclo-1,3,2-oxazaphosphoryl derivatives Expired - Lifetime US4238423A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP53137685A JPS5826919B2 (ja) 1978-11-07 1978-11-07 シクロ↓−１，３，２↓−オキサアザホスホル誘導体の製造法
JP53/137685 1978-11-07

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US4238423A true US4238423A (en) 1980-12-09

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US06/091,786 Expired - Lifetime US4238423A (en) 1978-11-07 1979-11-06 Process for preparing cyclo-1,3,2-oxazaphosphoryl derivatives

Country Status (12)

Country Link
US (1) US4238423A (de)
JP (1) JPS5826919B2 (de)
AU (1) AU515571B2 (de)
CA (1) CA1125781A (de)
CH (1) CH641186A5 (de)
DE (1) DE2944106C2 (de)
ES (1) ES485801A1 (de)
FR (1) FR2440953A1 (de)
GB (1) GB2034714B (de)
IT (1) IT1119426B (de)
NL (1) NL181433C (de)
SE (1) SE439636B (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623742A (en) 1981-03-24 1986-11-18 Asta-Werke Aktiengesellschaft Chemische Fabrik Oxazaphosphorin-4-thio-alkanesulphonic acids, and neutral salts thereof
US5258538A (en) * 1985-08-26 1993-11-02 Applied Biosystems, Inc. 2,3-disubstituted-1,3,2-oxazaphosphacycloalkanes as nucleic acid linking agents
US6187941B1 (en) * 1997-09-06 2001-02-13 Asta Medica Aktiengesellschaft Process for the preparation of oxazaphosphorine-2-amines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2644905A1 (de) * 1975-10-06 1977-04-14 Polska Akad Nauk Centrum Verfahren zur herstellung von optisch aktivem 2- eckige klammer auf bis-(2-chloraethyl)-amino eckige klammer zu -1-oxa-3-aza-2-phosphacyclohexanoxid-2

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2644905A1 (de) * 1975-10-06 1977-04-14 Polska Akad Nauk Centrum Verfahren zur herstellung von optisch aktivem 2- eckige klammer auf bis-(2-chloraethyl)-amino eckige klammer zu -1-oxa-3-aza-2-phosphacyclohexanoxid-2

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4623742A (en) 1981-03-24 1986-11-18 Asta-Werke Aktiengesellschaft Chemische Fabrik Oxazaphosphorin-4-thio-alkanesulphonic acids, and neutral salts thereof
US5258538A (en) * 1985-08-26 1993-11-02 Applied Biosystems, Inc. 2,3-disubstituted-1,3,2-oxazaphosphacycloalkanes as nucleic acid linking agents
US6187941B1 (en) * 1997-09-06 2001-02-13 Asta Medica Aktiengesellschaft Process for the preparation of oxazaphosphorine-2-amines

Also Published As

Publication number Publication date
SE7909157L (sv) 1980-05-08
IT7969163A0 (it) 1979-11-06
NL181433B (nl) 1987-03-16
GB2034714B (en) 1983-04-13
FR2440953B1 (de) 1984-09-14
JPS5564594A (en) 1980-05-15
CH641186A5 (de) 1984-02-15
CA1125781A (en) 1982-06-15
SE439636B (sv) 1985-06-24
NL7908116A (nl) 1980-05-09
NL181433C (nl) 1987-08-17
DE2944106A1 (de) 1980-05-08
AU515571B2 (en) 1981-04-09
IT1119426B (it) 1986-03-10
GB2034714A (en) 1980-06-11
FR2440953A1 (fr) 1980-06-06
AU5246879A (en) 1980-05-15
JPS5826919B2 (ja) 1983-06-06
ES485801A1 (es) 1980-07-01
DE2944106C2 (de) 1983-05-05

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